Journal of Alzheimer's Disease - Volume 54, issue 4

Authors: Parham, Christi L. | Shaw, Courtney | Auckland, Lisa D. | Dickeson, S. Kent | Griswold-Prenner, Irene | Bix, Gregory

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aβ) is the major component of plaques and consists of two prominent isoforms, Aβ40 and Aβ42 . As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aβ from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain …V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the α2 integrin and Aβ is a ligand for both α2β1 and αvβ1. Due to the known interaction of DV with α2β1 and α2β1’s requirement for Aβ deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with α2β1 binding by Aβ. Our study suggests that α2β1 mediates Aβ-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these α2β1 mediated neurotoxic effects suggesting that they or other α2β1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aβ40 and Aβ42 as further underscored by differing neuroprotective potencies of LG3 in each cell type. Show more

Keywords: Amyloid-β, cortical neurons, extracellular matrix, hippocampal neurons, integrins, signaling

DOI: 10.3233/JAD-160290

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1629-1647, 2016

Authors: Bonanni, Laura | Franciotti, Raffaella | Nobili, Flavio | Kramberger, Milica G. | Taylor, John-Paul | Garcia-Ptacek, Sara | Falasca, N. Walter | Famá, Francesco | Cromarty, Ruth | Onofrj, Marco | Aarsland, Dag | on behalf of the E-DLB study group

Article Type: Research Article

Abstract: Quantitative EEG (QEEG) has demonstrated good discriminative capacity for dementia with Lewy bodies (DLB) diagnosis as compared to Alzheimer’s disease (AD) with a predictive value of 100% in a single cohort study. EEG in DLB was characterized by a dominant frequency (DF) in pre-alpha (5.5–7.5 Hz), theta, or delta bands and DF variability (DFV) >1.2 Hz, frequency prevalence (FP) pre-alpha in >40% and FP alpha in <32% of the epochs. To validate the aforementioned QEEG findings in independent cohorts of clinically diagnosed DLB versus AD patients, we analyzed EEG traces of 79 DLB and 133 AD patients (MMSE >20) collected from four …European Centers. EEG traces from 19 scalp derivations were acquired as at least 10 min continuous signals and epoched in off-setting as series of 2-second-long epochs, subsequently processed by Fast Fourier Transform (frequency resolution 0.5 Hz). DLB patients showed EEG specific abnormalities in posterior derivations characterized by DF <8 Hz FP pre-alpha >50%, FP alpha <25%. DFV was >0.5 Hz. AD patients displayed stable alpha DF, DFV <0.5 Hz, FP pre-alpha <30%, and FP alpha >55%. DLB and AD differed for DF (p  < 10–6 ), DFV (p  < 0.05), FP pre-alpha (p  < 10–12 ) and FP alpha (p  < 10–12 ). Discriminant analysis detected specific cut-offs for every EEG mathematical descriptor; DF = 8, DFV = 2.2 Hz, FP pre-alpha=33%, FP alpha = 41% for posterior derivations. If at least one of the cut-off values was met, the percentage of DLB and AD patients correctly classified was 90% and 64%, respectively. The findings in this multicenter study support the validity of QEEG analysis as a tool for diagnosis in DLB patients. Show more

Keywords: Dementia with Lewy bodies, quantitative EEG

DOI: 10.3233/JAD-160435

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1649-1657, 2016

Authors: Gourmaud, Sarah | Mouton-Liger, François | Abadie, Claire | Meurs, Eliane F. | Paquet, Claire | Hugon, Jacques

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR–/– ) mice neurons, …we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR–/– neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models. Show more

Keywords: Alzheimer’s disease, amyloid-beta, JNK, neuronal death, PKR, therapeutic strategy

DOI: 10.3233/JAD-160509

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1659-1670, 2016

Authors: Musunuri, Sravani | Khoonsari, Payam Emami | Mikus, Maria | Wetterhall, Magnus | Häggmark-Mänberg, Anna | Lannfelt, Lars | Erlandsson, Anna | Bergquist, Jonas | Ingelsson, Martin | Shevchenko, Ganna | Nilsson, Peter | Kultima, Kim

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Methods: Here we …used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD. Show more

Keywords: Alzheimer’s disease, endocytosis, exocytosis, exosomes, extracellular vesicles, immobilized, chemistry antibodies, mass spectrometry

DOI: 10.3233/JAD-160271

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1671-1686, 2016

Article Type: Other

DOI: 10.3233/JAD-160799

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1687-1690, 2016

Article Type: Other

DOI: 10.3233/JAD-160963

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1691-1702, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1703-1720, 2016